Kidney Week

Abstract: TH-PO0046

Physiological Roles of KCC4 in Renal Salt Reabsorption and Potassium Conservation

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Chen, Yu-Jen, Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States

Yu-Jen Chen, MD

• Hsieh, Chiao-Hui, Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States

Chiao-Hui Hsieh, PhD

• Morrison, Emily, Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States

Emily Morrison

• Cheng, Chih-Jen, Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States

Chih-Jen Cheng, MD, PhD

Background

Three potassium chloride co-transporters (KCC) are expressed in the kidneys, yet their precise roles in renal sodium and potassium handling remain unclear.

Methods

In this study, we generated kidney-specific knockout mouse models for Kcc1 (Kcc1^-/-), Kcc4 (Kcc4^-/-), and a double knockout (Kcc1^-/-/Kcc4^-/-) and validated these models using novel, specific monoclonal antibodies against mouse Kcc1 and Kcc4.

Results

While these models showed no significant renal phenotype under normal or low-salt diets, the physiological importance of Kcc4 became evident through two distinct mechanisms. First, crossing Kcc4^-/- mice with kidney-specific Clc-k2-knockout (Clc-k2^-/-) mice resulted in a further reduction of Nkcc2 and Ncc activity and worsened renal function compared to Clc-k2^-/- mice alone. Second, under dietary potassium deprivation, both Kcc4^-/- and Kcc1^-/-/Kcc4^-/- mice exhibited significantly lower serum potassium levels and higher urinary potassium excretion than wild-type controls. This defect was associated with normal levels of Ncc phosphorylation but a failure to upregulate the expression of H⁺, K⁺-ATPase.

Conclusion

These findings suggest that Kcc4 serves as a critical compensatory basolateral chloride access in the thick ascending limb and the distal convoluted tubule for salt reabsorption when the dominant chloride channel, Clc-k2, is deficient. Furthermore, while Kcc4 is not essential for hypokalemia-induced Ncc activation, it is critical for maintaining H⁺, K⁺-ATPase-mediated potassium conservation.

Acknowledgment

This study is supported by grants from the National Institutes of Health, U.S.A. (DK134420 to CJC).

Funding

• NIDDK Support